Anaphylaxis slow reacting substances

Slow-reacting substance of anaphylaxis (SRS-A) is a mixture of leukotrienes C4, D4, and E4. This mixture of leukotrienes is a potent constrictor of the bronchial ait-way musculature. These leukotrienes together with leukotriene B4 also cause vascular permeabifity and attraction and activation of leukocytes and ate important regulators in many diseases involving inflammatory or... 

SOZ Serum-opsonized zymosan SP Sulphapyridine SR Systemic reaction sr Sarcoplasmic reticulum SRBC Sheep red blood cells SRS Slow-reacting substance SRS-A Slow-reacting substance of anaphylaxis STZ Streptozotocin Sub P Substance P... 

In the 1930s an unknown material was hypothesized that was proposed to cause a slow and sustained contraction of smooth muscle. It was named the slow reacting substance (SRS). By 1940 a similar substance was reported to be found in guinea pig lungs and was called the slow reacting substance of anaphylaxis (SRS-A). Over the next 40 years, while no one could isolate, characterize, or synthesize this mate-... 

SRS-A Lung tissue (Slow-reacting substance of anaphylaxis) Contraction of smooth muscle acidic polypeptide... 

Leukotrienes (LTA, LTB LTC, LTD, and LTE ) are synthesized from arachi-donic acid by a cascade of enzymes that include 5-lipoxygenase (5-LOX), 5-lipoxy-genase-activating protein (FLAP), and leukotriene C4 synthase (LTC synthase) (79,80). The leukotriene LTA is synthesized by 5-LOX in the first step and is an unstable precursor that is then enzymatically converted to LTB or LTC (80,81), which can subsequently be metabolized to LTD and LTE. LTC, LTD, and LTE are the components of the slow-reacting substance of anaphylaxis. These moieties, particularly LTC and LTD, are active forms of CysLTs that interact with the G protein-coupled cysteinyl leukotriene receptors (CysLtrl and CysLtr2) (70,81,82). Once engaged, the activated CysLtrs receptors stimulate the secretion of mucus and induce edema and bronchoconstriction (81). 

Leukotrienes increase capillary permeability and serve as chemotactic factors for neutrophil granulocytes. As "slow-reacting substances of anaphylaxis," they are involved in allergic reactions (p. 326) together with PG, they evoke the spectrum of characteristic inflammatory symptoms redness, heat, swelling, and pain. 

Mechanism of Action An antiasthmatic and antiallergic agent that prevents mast cell release of histamine, leukotrienes, and slow-reacting substances of anaphylaxis by inhibiting degranulation after contact with antigens. Therapeutic Effect Helps prevent symptoms of asthma, allergic rhinitis, mastocytosis, and exercise-induced bron-chospasm. 

Histamine is released from mast cells in antigen-antibody reactions, as in anaphylaxis and allergy, which are the most widely known physiological reactions to histamine. However, these potentially fatal reactions are not caused by histamine alone. Other agents present in mast cells, such as serotonin, acetylcholine, bradykinin (a nonapeptide), and a slow-reacting substance or leukotriene (see chapter 8) also contribute. In the stomach, where histamine induces acid secretion, its release seems to be regulated by the peptide hormone pentagastrin. 

LTC4 and LTD4 are potent bronchoconstrictors and are recognized as the primary components of the slow-reacting substance of anaphylaxis (SRS-A) that is secreted in asthma and anaphylaxis. There are four current approaches to antileukotriene drug development 5-LOX enzyme inhibitors, leukotriene-receptor antagonists, inhibitors of FLAP, and phospholipase A2 inhibitors. 

Kalinger, M., Orange, R. P., Austen, K. F. Immunological release of histamine and slow reacting substance of anaphylaxis from human lung. J. exp. Med. 136, 556 (1972)... 

Eosinophils are attracted by proteins released by T cells, mast cells and basophils [eosinophil chemotactic factor of anaphylaxis (ECF-A)]. They bind schistosomulae coated with IgG or IgE, degranulate and release major basic protein, which is toxic. Eosinophils also release histaminase and aryl sulfatase, which inactivates histamine and Slow reacting substance of anaphylaxis (SRS-A). This results in antiinflammatory effects and inhibits migration of granulocytes to the site of injury. 

Buckle DR, Outred DJ, Ross JW, Smith H, Smith RJ, Spicer BA, Gasson BC (1979) Aryloxyalkyloxy- and aralkyloxy-4-hydroxy-3-nitrocoumarins which inhibit histamine release in the rat and also antagonize the effects of a slow reacting substance of anaphylaxis. J Med Chem 22(2) 158... 

At about the same time, a synthesis of leukotriene-A, also termed SRS-A ( slow reacting substance of anaphylaxis ), which made use of the Wittig olefmation was described77). The ylide of 100 is reacted with ethyl 5-formyl-2,4-pentadienoate 101 to give the ( , , Z, Z)- tetraenoic ester 102. Reduction and mesylation of 102, subsequent conversion into the sulfonium salt, and treatment of the latter with a base yields a sulfonium ylide which is reacted with methyl 4-formylbutanoate 69 to the epoxy-tetraenoic ester 103. After separation of the cis-epoxide by HPLC, 103 was treated with the S-trimethylsilyl derivative of glutathione dimethyl ester N-trifluoroacet-amide. The diastereomeric products thus obtained were separated by means of HPLC and hydrolyzed to 104 77) (Scheme 18). 

Corey, E.J., Albright, ).0., Burton, A.E. and Hashimoto, S. (1980) Chemical and enzymic syntheses of 5-HPETE, a key biological precursor of slow-reacting substance of anaphylaxis (SRS), and 5-HETE. Journal of the American Chemical Society, 102,1435-1436. 

Most cases of contact urticaria are of non-immunolo-gical origin, presumably due to the direct release of histamine, slow-reacting substance of anaphylaxis (SRS-A), bradykinin, or other vasoactive substances. Topical drugs and ingredients of cosmetics that have caused non-immunological contact urticaria are listed in Table 2. 

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